Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression

TLDR

Chemotherapy delivered by nanocarriers has only modestly improved survival in pancreatic ductal adenocarcinoma, so engaging the immune response could be transformative. We aim to create a nano‑enabled strategy that induces immunogenic cell death and blocks the IDO pathway to elicit robust anti‑PDAC immunity. The approach uses indoximod‑conjugated phospholipid nanovesicles that encapsulate mesoporous silica nanoparticles loaded with oxaliplatin, enabling simultaneous delivery of IDO inhibition and ICD induction via vaccination, direct injection, or intravenous targeting of orthotopic tumors. The treatment achieved significant tumor reduction or eradication by recruiting cytotoxic T lymphocytes while decreasing Foxp3⁺ regulatory T cells.

Abstract

While chemotherapy delivery by nanocarriers has modestly improved the survival prospects of pancreatic ductal adenocarcinoma (PDAC), additional engagement of the immune response could be game changing. We demonstrate a nano-enabled approach for accomplishing robust anti-PDAC immunity in syngeneic mice through the induction of immunogenic cell death (ICD) as well as interfering in the immunosuppressive indoleamine 2,3-dioxygenase (IDO) pathway. This is accomplished by conjugating the IDO inhibitor, indoximod (IND), to a phospholipid that allows prodrug self-assembly into nanovesicles or incorporation into a lipid bilayer that encapsulates mesoporous silica nanoparticles (MSNP). The porous MSNP interior allows contemporaneous delivery of the ICD-inducing chemotherapeutic agent, oxaliplatin (OX). The nanovesicles plus free OX or OX/IND-MSNP induce effective innate and adaptive anti-PDAC immunity when used in a vaccination approach, direct tumor injection or intravenous biodistribution to an orthotopic PDAC site. Significant tumor reduction or eradication is accomplishable by recruiting cytotoxic T lymphocytes, concomitant with downregulation of Foxp3+ T cells.